{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:57:58Z","timestamp":1753891078028,"version":"3.41.2"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T00:00:00Z","timestamp":1696550400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Thymic epithelial cells (TECs) are essential for T cell development in the thymus, yet the mechanisms governing their differentiation are not well understood. Lin28, known for its roles in embryonic development, stem cell pluripotency, and regulating cell proliferation and differentiation, is expressed in endodermal epithelial cells during embryogenesis and persists in adult epithelia, implying postnatal functions. However, the detailed expression and function of Lin28 in TECs remain unknown. In this study, we examined the expression patterns of <jats:italic>Lin28<\/jats:italic> and its target <jats:italic>Let-7g<\/jats:italic> in fetal and postnatal TECs and discovered opposing expression patterns during postnatal thymic growth, which correlated with FOXN1 and MHCII expression. Specifically, <jats:italic>Lin28b<\/jats:italic> showed high expression in MHCII<jats:sup>hi<\/jats:sup> TECs, whereas <jats:italic>Let-7g<\/jats:italic> was expressed in MHCII<jats:sup>lo<\/jats:sup> TECs. Deletion of <jats:italic>Lin28a<\/jats:italic> and <jats:italic>Lin28b<\/jats:italic> specifically in TECs resulted in reduced MHCII expression and overall TEC numbers. Conversely, overexpression of <jats:italic>Lin28a<\/jats:italic> increased total TEC and thymocyte numbers by promoting the proliferation of MHCII<jats:sup>lo<\/jats:sup> TECs. Additionally, our data strongly suggest that <jats:italic>Lin28<\/jats:italic> and <jats:italic>Let-7g<\/jats:italic> expression is reliant on FOXN1 to some extent. These findings suggest a critical role for Lin28 in regulating the development and differentiation of TECs by modulating MHCII expression and TEC proliferation throughout thymic ontogeny and involution. Our study provides insights into the mechanisms underlying TEC differentiation and highlights the significance of Lin28 in orchestrating these processes.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1261081","type":"journal-article","created":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T11:44:16Z","timestamp":1696592656000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lin28 regulates thymic growth and involution and correlates with MHCII expression in thymic epithelial cells"],"prefix":"10.3389","volume":"14","author":[{"given":"Shiyun","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy R.","family":"Manley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,10,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nature02871","article-title":"The functions of animal microRNAs","volume":"431","author":"Ambros","year":"2004","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0092-8674(00)81906-6","article-title":"The cold shock domain protein LIN-28 controls developmental timing in C. elegans and is regulated by the lin-4 RNA","volume":"88","author":"Moss","year":"1997","journal-title":"Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/35002607","article-title":"The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans","volume":"403","author":"Reinhart","year":"2000","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S0012-1606(03)00126-X","article-title":"Conservation of the heterochronic regulator Lin-28, its developmental expression and microRNA complementary sites","volume":"258","author":"Moss","year":"2003","journal-title":"Dev Biol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/35040556","article-title":"Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA","volume":"408","author":"Pasquinelli","year":"2000","journal-title":"Nature"},{"key":"B6","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1126\/science.1154040","article-title":"Selective blockade of microRNA processing by Lin28","volume":"320","author":"Viswanathan","year":"2008","journal-title":"Science"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1759","article-title":"A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment","volume":"10","author":"Rybak","year":"2008","journal-title":"Nat Cell Biol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.cell.2011.08.033","article-title":"The Lin28\/let-7 axis regulates glucose metabolism","volume":"147","author":"Zhu","year":"2011","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1261\/rna.034538.112","article-title":"Lin28-mediated control of let-7 microRNA expression by alternative TUTases Zcchc11 (TUT4) and Zcchc6 (TUT7)","volume":"18","author":"Thornton","year":"2012","journal-title":"RNA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1634\/stemcells.2008-0720","article-title":"Genetic analysis of the role of the reprogramming gene LIN-28 in human embryonic stem cells","volume":"27","author":"Darr","year":"2009","journal-title":"Stem Cells"},{"key":"B11","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1634\/stemcells.22-1-51","article-title":"The transcriptome profile of human embryonic stem cells as defined by SAGE","volume":"22","author":"Richards","year":"2004","journal-title":"Stem Cells"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1242\/dev.091777","article-title":"Stem cell metabolism in tissue development and aging","volume":"140","author":"Shyh-Chang","year":"2013","journal-title":"Development"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1216557","article-title":"Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis","volume":"335","author":"Yuan","year":"2012","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20141510","article-title":"Lin28b promotes fetal B lymphopoiesis through the transcription factor Arid3a","volume":"212","author":"Zhou","year":"2015","journal-title":"J Exp Med"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20151912","article-title":"Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis","volume":"213","author":"Rowe","year":"2016","journal-title":"J Exp Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.cell.2009.10.014","article-title":"An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation","volume":"139","author":"Iliopoulos","year":"2009","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2012.06.001","article-title":"How does Lin28 let-7 control development and disease","volume":"22","author":"Thornton","year":"2012","journal-title":"Trends Cell Biol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/ng.392","article-title":"Lin28 promotes transformation and is associated with advanced human Malignancies","volume":"41","author":"Viswanathan","year":"2009","journal-title":"Nat Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.4161\/cc.6.21.4845","article-title":"Let-7 prevents early cancer progression by suppressing expression of the embryonic gene HMGA2","volume":"6","author":"Park","year":"2007","journal-title":"Cell Cycle"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ng.593","article-title":"Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies","volume":"42","author":"Zhu","year":"2010","journal-title":"Nat Genet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1423","article-title":"Fetal deficiency of lin28 programs life-long aberrations in growth and glucose metabolism","volume":"31","author":"Shinoda","year":"2013","journal-title":"Stem Cells"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2008.07.007","article-title":"The let-7 family of microRNAs","volume":"18","author":"Roush","year":"2008","journal-title":"Trends Cell Biol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2006.10.040","article-title":"Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C","volume":"127","author":"Ruby","year":"2006","journal-title":"elegans Cell"},{"key":"B24","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.stem.2013.03.005","article-title":"Lin28: primal regulator of growth and metabolism in stem cells","volume":"12","author":"Shyh-Chang","year":"2013","journal-title":"Cell Stem Cell"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1745","article-title":"Distinct expression patterns predict differential roles of the miRNA-binding proteins, Lin28 and Lin28b, in the mouse testis: studies during postnatal development and in a model of hypogonadotropic hypogonadism","volume":"154","author":"Gaytan","year":"2013","journal-title":"Endocrinology"},{"key":"B26","doi-asserted-by":"publisher","first-page":"15683","DOI":"10.1038\/srep15683","article-title":"Testicular expression of the Lin28\/let-7 system: Hormonal regulation and changes during postnatal maturation and after manipulations of puberty","volume":"5","author":"Sangiao-Alvarellos","year":"2015","journal-title":"Sci Rep"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/ng.382","article-title":"et al: Genetic variation in LIN28B is associated with the timing of puberty","volume":"41","author":"Ong","year":"2009","journal-title":"Nat Genet"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193188","article-title":"Thymic epithelial cell-derived signals control B progenitor formation and proliferation in the thymus by regulating Let-7 and Arid3a","volume":"13","author":"Xiao","year":"2018","journal-title":"PloS One"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.01.014","article-title":"RAS is regulated by the let-7 microRNA family","volume":"120","author":"Johnson","year":"2005","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"1860","DOI":"10.1038\/srep01860","article-title":"Transcriptome sequencing of neonatal thymic epithelial cells","volume":"3","author":"St-Pierre","year":"2013","journal-title":"Sci Rep"},{"key":"B31","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/nmeth.3485","article-title":"miRWalk2.0: a comprehensive atlas of microRNA-target interactions","volume":"12","author":"Dweep","year":"2015","journal-title":"Nat Methods"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbi.2011.05.002","article-title":"miRWalk\u2013database: prediction of possible miRNA binding sites by \u201cwalking\u201d the genes of three genomes","volume":"44","author":"Dweep","year":"2011","journal-title":"J Biomed Inf"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/nri1331","article-title":"Developing a new paradigm for thymus organogenesis","volume":"4","author":"Blackburn","year":"2004","journal-title":"Nat Rev Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1242\/dev.059998","article-title":"Mechanisms of thymus organogenesis and morphogenesis","volume":"138","author":"Gordon","year":"2011","journal-title":"Development"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/S1877-1173(10)92005-X","article-title":"Transcriptional regulation of thymus organogenesis and thymic epithelial cell differentiation","volume":"92","author":"Manley","year":"2010","journal-title":"Prog Mol Biol Transl Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1126\/science.272.5263.886","article-title":"Two genetically separable steps in the differentiation of thymic epithelium","volume":"272","author":"Nehls","year":"1996","journal-title":"Science"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-05-156265","article-title":"Foxn1 is required to maintain the postnatal thymic microenvironment in a dosage-sensitive manner","volume":"113","author":"Chen","year":"2009","journal-title":"Blood"},{"key":"B38","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/1471-213X-7-69","article-title":"Specific expression of lacZ and cre recombinase in fetal thymic epithelial cells by multiplex gene targeting at the Foxn1 locus","volume":"7","author":"Gordon","year":"2007","journal-title":"BMC Dev Biol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/immu.200310005","article-title":"Transgenic mice with hematopoietic and lymphoid specific expression of Cre","volume":"33","author":"de Boer","year":"2003","journal-title":"Eur J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1242\/dev.120543","article-title":"Lin28 promotes the proliferative capacity of neural progenitor cells in brain development","volume":"142","author":"Yang","year":"2015","journal-title":"Development"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2012.10.025","article-title":"Investigation of peripubertal expression of Lin28a and Lin28b in C57BL\/6 female mice","volume":"365","author":"Grieco","year":"2013","journal-title":"Mol Cell Endocrinol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-0436.1973.tb00143.x","article-title":"Athymic development in the mouse","volume":"1","author":"Pantelouris","year":"1973","journal-title":"Differentiation"},{"key":"B43","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1242\/dev.042895","article-title":"LIN28 alters cell fate succession and acts independently of the let-7 microRNA during neurogliogenesis","volume":"137","author":"Balzer","year":"2010","journal-title":"vitro Dev"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20092144","article-title":"Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation","volume":"207","author":"Nishikawa","year":"2010","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00019","article-title":"Post-Aire maturation of thymic medullary epithelial cells involves selective expression of keratinocyte-specific autoantigens","volume":"3","author":"Wang","year":"2012","journal-title":"Front Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3146","article-title":"Let-7 microRNAs target the lineage-specific transcription factor PLZF to regulate terminal NKT cell differentiation and effector function","volume":"16","author":"Pobezinsky","year":"2015","journal-title":"Nat Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1261081\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,6]],"date-time":"2023-10-06T11:44:27Z","timestamp":1696592667000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1261081\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,6]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2023.1261081"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1261081","relation":{},"ISSN":["1664-3224"],"issn-type":[{"type":"electronic","value":"1664-3224"}],"subject":[],"published":{"date-parts":[[2023,10,6]]},"article-number":"1261081"}}